Thalidomide (N-α-phthalimidoglutarimide) is an infamous drug known for its potent teratogenic side effects. Thalidomide was first synthesized in Germany in 1954 and was marketed from 1957 worldwide as a non-barbiturate, non-addictive, non-toxic sedative and anti-nausea medication. Thalidomide was withdrawn from the world market in 1961 due to the development of severe congenital abnormalities in babies born to mothers using it for morning sickness. Thalidomide caused thousands of cases of limb reduction anomalies, including phocomelia (absence of the long bones in the forelimb) or amelia (a complete absence of the forelimb) in the children of pregnant women in the 1950s and 1960s. Other phenotypic malformations were also commonly seen including eye, ear, heart, gastrointestinal and kidney defects. Analogs of thalidomide are also commonly teratogenic.
Subsequent use, and research into the underlying mechanisms of action of thalidomide, found it perpetuates inflammatory and immunomodulatory characteristics. The immunological and inflammatory basis for the clinical efficacy of thalidomide lies in thalidomide's ability to inhibit the synthesis of tumor necrosis factor alpha (TNF-α). TNF-α and family members play pivotal roles in a variety of physiological and pathological processes, which include cell proliferation and differentiation, apoptosis, the modulation of immune responses and induction of inflammation. Thalidomide has also been shown to alter the density of TNF-α induced adhesion molecules on leukocytes in order to prevent the binding of the pro-inflammatory cytokine, which may contribute to the anti-inflammatory properties of the drug.
Thalidomide has additionally been found to successfully inhibit the formation of new blood vessels, a process known as angiogenesis. This led to the hypothesis that a loss of normal blood vessel formation could have caused the damage seen in embryos following thalidomide exposure. Since then, thalidomide has been shown to inhibit new vessel formation in chicken embryos and also both the rat aortic ring assay, and in in vitro cultures of human umbilical vein endothelial cells by modulation of the actin cytoskeleton. Thalidomide has been shown to treat hereditary hemorrhagic telangiectasia in human patients by stabilizing leaky, malformed vessels and inhibiting their formation. Thalidomide analogs have also been demonstrated to be anti-angiogenic in chicken embryo assays and zebrafish embryos. Thalidomide's combined anti-angiogenic and anti-inflammatory properties likely lead to its anti-cancer effects and efficacy in the treatment of multiple myeloma as well as documented activity in other cancers.
A need exists for thalidomide analogs that exhibit clinical potential (e.g., anti-inflammatory and/or anti-angiogenic activity) without teratogenicity and/or that have more potency and/or fewer side effects than those of currently used thalidomide analogs.